Etanercept versus etanercept plus methotrexate: a registry-based study suggesting that the combination is clinically more efficacious

Etanercept can be used both as monotherapy and in combination with methotrexate (MTX), but direct comparisons of these two options have not yet been reported. In order to compare the results seen in actual practice between these two options, clinical data on 97 patients followed in the Stockholm TNFα Follow-Up Registry were analysed. In 57 of these patients etanercept was added to previously started MTX while the others were treated with etanercept alone. The two groups had similar levels of disease activity at baseline. After 3 months, a significantly lower mean disease activity score (28-joint count-based disease activity score) was attained by the patients on etanercept plus MTX. In this group, the number of patients achieving European League Against Rheumatism-defined remission was also significantly greater. Other disease outcomes showed non-significant trends in the same direction. These data suggest that the combination of etanercept plus MTX is clinically more efficacious than etanercept alone

Rheumatoid arthritis : Pharmacological modulation of cytokines - aspects of clinical response and endocrine regulation

Rheumatoid arthritis (RA) is a systemic inflammatory disease primarily affecting the joints. In the pathogenesis several cells of the immune systeme and messengers of the immune systeme, cytokines, are important. In this thesis, the cytokine-modulating effects of two different treatments in RA, gold sodium thiomalate (GSTM) and the TNF-antagonist infliximab, are investigated. Further genetic factors potentially predicting clinical response to another TNF-antagonist, etanercept, are presented. Finally, the effect of TNF-antagonists on the hormone levels of the adrenal and gonadal axes is demonstrated. The mechanism of action of GSTM is not fully understood. We studied 20 patients with RA during treatment with GSTM. The numbers of IL-6-, IL-10- and IFNgamma-producing cells measured with ELISPOT were significantly increased after four weeks treatment with GSTM, as was serum concentrations of IL-10. In addition a higher IL-10 production from peripheral blood mononuclear cells was recorded in patients without a subsequent skin rash. There was no correlation between clinical response and cytokine production. In conclusion, GSTM seems to have immunoregulatory properties that may be important for the therapeutic effect in RA. The effect of TNF-antagonists on cytokine expression in the synovial membrane may be of relevance as additional therapeutic targets may be identified. We studied the effect of the TNF-antagonist infliximab on the synovial expression of TNF, IL-1alpha, IL-1beta, IFNgamma and IL-15 with immunohistochemistry. IL-15 is still present in the synovial tissue after treatment with infliximab as a remaining potential target. There was no correlation between synovial expression of IL-15 and response to therapy, but expression of TNF at baseline was exclusively seen in patients with good response to infliximab. Genetic factors, such as HLADRB1/shared epitope or cytokine gene promoter polymorphisms, relevant to RA, were investigated concerning correlation with clinical response to the TNF-antagonist etanercept. The combination of the alleles 308TNFG/G and 1087IL-10G/G was correlated with a good response, compared with all other combinations. This combination may correlate with a presumed functional phenotype with a low immune response. Both adrenal and gonadal axes are reported to be downregulated in RA with a decreased responsiveness to inflammatory stimuli. This down-regulation has been suggested to be the effect of proinflammatory cytokines. We studied ACTH, cortisol, DHEAS, LH, testosterone and estradiol during two years treatment with TNF-antagonists. An individual stability in hormone levels was recorded, with no effect of decreased disease activity on this stability. DHEAS increased in females without prednisolone treatment, with a correlation with improved physical function, possibly relevant to other effective treatments. A subset of women with low adrenal hormone levels had a disease onset at a young age. Presuming a stable individual hormonal homeostasis, these low adrenal hormone levels may even precede disease onset. In conclusion, studies on cytokine-modulating treatment strategies in RA may provide information on mechanism of action and give further insight in potential pathogenetic mechanisms

Prevalence of sustained remission in rheumatoid arthritis: impact of criteria sets and disease duration, a Nationwide Study in Sweden

Objectives The aims of this national study in Sweden of patients with RA were to: examine the prevalence of sustained remission (SR), that is, remission lasting for at least 6 months; compare the prevalence of SR in patients with early RA and established RA; study the timing of onset of and time spent in SR; and study possible predictors of SR. Methods Adult patients with RA included in the Swedish Rheumatology Quality registry were studied. The registry was searched for patients fulfilling remission criteria: DAS28-ESR, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and ACR/EULAR remission for at least 6 months. Early RA was defined as symptom duration ⩽6 months at inclusion in the Swedish Rheumatology Quality. Results Of 29 084 patients, 12 193 (41.9%) reached DAS28 SR at some time point during follow-up compared with 6445 (22.2%), 6199 (21.3%) and 5087 (17.5%) for CDAI, SDAI and ACR/EULAR SR, respectively. SR was more common in early RA (P < 0.001). The median time from symptom onset to SR was 1.9, 2.4, 2.4 and 2.5 years according to DAS28, CDAI, SDAI and ACR/EULAR criteria, respectively. Lower age, male sex and milder disease characteristics were associated with SR. Conclusion The majority of patients in this nationwide study never reached SR. Patients with early RA are more likely to reach SR than patients with established RA

Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial.

OBJECTIVE: To estimate the incremental cost-effectiveness of infliximab versus conventional combination treatment over 21 months in patients with methotrexate-refractory early rheumatoid arthritis. METHODS: In this multicentre, two-arm, parallel, randomised, active-controlled, open-label trial, rheumatoid arthritis patients with <1 year symptom duration were recruited from 15 rheumatology clinics in Sweden between October 2002 and December 2005. After 3-4 months of methotrexate monotherapy, patients not achieving low disease activity were randomised to addition of infliximab or sulfasalazine+hydroxychloroquine (conventional treatment group). Costs of drugs, healthcare use, and productivity losses were retrieved from nationwide registers, while EuroQol 5-Dimensions utility was collected quarterly. RESULTS: Of 487 patients initially enrolled, 128 and 130 were randomised to infliximab and conventional treatment, respectively. The infliximab group accumulated higher drug and healthcare costs (€27 487 vs €10 364; adjusted mean difference €16 956 (95% CI 14 647 to 19 162)), while productivity losses did not differ (€33 804 vs €29 220; €3961 (95% CI -3986 to 11 850)), resulting in higher societal cost compared to the conventional group (€61 291 vs €39 584; €20 916 (95% CI 12 800 to 28 660)). Mean accumulated quality-adjusted life-years (QALYs) did not differ (1.10 vs 1.12; adjusted mean difference favouring infliximab treatment 0.01 (95% CI -0.07 to 0.08)). The incremental cost-effectiveness ratios for the infliximab versus conventional treatment strategy were €2 404 197/QALY from the societal perspective and €1 948 919/QALY from the healthcare perspective. CONCLUSIONS: In early, methotrexate-refractory rheumatoid arthritis, a treatment strategy commencing with addition of infliximab, as compared to sulfasalazine+hydroxychloroquine, was not cost-effective over 21 months at willingness to pay levels generally considered acceptable. TRIAL REGISTRATION NUMBER: NCT00764725

Biological vs Conventional Combination Treatment and Work Loss in Early Rheumatoid Arthritis A Randomized Trial

IMPORTANCE The introduction of biological tumor necrosis factor inhibitors has improved the treatment of rheumatoid arthritis (RA) but at a substantial cost. These drugs have been shown to lead to superior radiological outcomes compared with a combination of conventional disease-modifying antirheumatic drugs over 2 years. OBJECTIVE To investigate whether radiological superiority translates into better work loss outcomes. DESIGN, SETTING, AND PARTICIPANTS Multicenter, 2-arm, parallel, randomized, active-controlled, open-label trial. Patients with early RA (symptom duration <1 year) were recruited from 15 rheumatology clinics in Sweden from October 1, 2002, through December 31, 2005. The study population was restricted to working-age patients (aged <63 years). INTERVENTIONS Patients who did not achieve low disease activity after 3 to 4 months of methotrexate therapy were randomized to receive additional biological treatment with infliximab or conventional combination treatment with sulfasalazine plus hydroxychloroquine. MAIN OUTCOMES AND MEASURES Monthly sick leave and disability pension days 21 months after randomization retrieved from the nationwide Swedish Social Insurance Office register. Main analyses were by intention to treat, including all patients, and adjusted for baseline sick leave and disability pension. RESULTS Of 204 eligible patients, 105 were randomized to biological and 99 to conventional treatment. Seven patients in the biological and 4 in the conventional treatment group never received the study drug, and 72 and 52 patients, respectively, followed the study per protocol for 21 months. The baseline mean (SD) work loss was 17 (13) d/mo (median, 16 d/mo) in both groups (mean difference, 0.6 d/mo; 95% CI, -3.0 to 3.9). The mean changes in work loss at 21 months were -4.9 d/mo in the biological and -6.2 d/mo in the conventional treatment group (adjusted mean difference, 1.6 d/mo; 95% CI, -1.2 to 4.4). Including only patients receiving at least 1 dose of assigned treatment, the adjusted mean difference was 1.5 d/mo (95% CI, -1.5 to 4.4), and in per-protocol analysis the adjusted mean difference was 0.3 d/mo (95% CI, -2.8 to 3.8). CONCLUSIONS AND RELEVANCE The radiological superiority of biological compared with conventional combination therapy did not translate into better work loss outcomes in patients with early RA who had experienced an insufficient response to methotrexate